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From iron metabolism in parasitic protists to drug discovery
Arbon, Dominik
Iron is essential for the correct function of various biochemical processes. Most living organisms developed elaborate strategies for homeostasis of this metal, including specific approaches for its acquisition and trafficking, to incorporate it into different pathways in various cellular compartments. Across the domain of parasitic protists, iron plays a crucial role in the interaction between pathogen and its host, where the struggle for scavenging available iron is a basis for nutritional immunity. This work summarizes the current knowledge about iron acquisition and trafficking in a spectrum of facultative and obligative unicellular parasites, with experimental discoveries of the iron acquisition strategies and response to iron-deficient conditions in parasitic protists Naegleria fowleri and Acanthamoeba castellanii. Based on this, the validity of exploiting iron chelation therapy is theoretically and experimentally assessed. Further work focuses on the utilization of mitochondrial targeting as a method of improving the potential of therapeutic compounds, including iron chelators, and describing their action in vitro and in vivo against a range of parasites.
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Treatment options for untreatable amoeba Naegleria fowleri
Veselý, Martin ; Mach, Jan (advisor) ; Arbon, Dominik (referee)
Naegleria fowleri is a free-living protist which can penetrate the body of a previously healthy person and cause meningoencephalitis. The rapid course, disproportionately strong immune response and the lack of effective drugs are the reasons why this disease almost always ends fatally. Due to the relative rarity of this disease, it is not lucrative for pharmaceutical companies to develop a completely new drug. The only way to search for effective drugs is to test those that have already been approved for another purpose. However, clinical tests are not possible due to the low morbidity and rapid course of the disease, and research in this area is thus limited to animal models of the disease and evaluation of the effect of drugs against the pathogen in vitro. Currently used medication includes drugs that are highly toxic or poorly penetrate the site of inflammation. In the future, more effective chemotherapy against N. fowleri and more gentle towards patient could be used. This work summarizes knowledge about pathogenic amoeba, currently used drugs and presents new experimentally tested therapeutics.
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From iron metabolism in parasitic protists to drug discovery
Arbon, Dominik ; Šuťák, Róbert (advisor) ; De Koning, Harry P. (referee) ; Petrák, Jiří (referee)
Iron is essential for the correct function of various biochemical processes. Most living organisms developed elaborate strategies for homeostasis of this metal, including specific approaches for its acquisition and trafficking, to incorporate it into different pathways in various cellular compartments. Across the domain of parasitic protists, iron plays a crucial role in the interaction between pathogen and its host, where the struggle for scavenging available iron is a basis for nutritional immunity. This work summarizes the current knowledge about iron acquisition and trafficking in a spectrum of facultative and obligative unicellular parasites, with experimental discoveries of the iron acquisition strategies and response to iron-deficient conditions in parasitic protists Naegleria fowleri and Acanthamoeba castellanii. Based on this, the validity of exploiting iron chelation therapy is theoretically and experimentally assessed. Further work focuses on the utilization of mitochondrial targeting as a method of improving the potential of therapeutic compounds, including iron chelators, and describing their action in vitro and in vivo against a range of parasites.
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Current chemotherapy of protozoal parasitoses.
Valach, Marek ; Hrdý, Ivan (advisor) ; Arbon, Dominik (referee)
This work is devoted to the process of chemotherapy of diseases caused by parasitic protozoa. Even though being often shadowed by bacterial or viral infections, protozoan caused diseases affect hundreds of millions of people every year, especially in tropical and subtropical regions of the developing world. This great burden placed on inhabitants of these countries highlights the need for functional chemotherapeutics against these diseases, because vaccination is not yet an option. The goal of successful chemotherapy is either elimination or suppression of the parasite in the patient by exploiting its weaknesses in its life cycle or differences in physiology between the parasite and the host. The aim of this work is to provide an overview of chemotherapeutics currently approved for the treatment four most prevalent parasite diseases. The diseases are clearly described in the terms of symptoms, their socioeconomical impact and lifecycle of the parasite. An emphasis is placed on the description of mode of action of each chemotherapeutical agent and on mechanism allowing the parasite to resist the drug.
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Iron metabolism in Naegleria gruberi
Arbon, Dominik ; Šuťák, Róbert (advisor) ; Krijt, Matyáš (referee)
The metabolism of iron ions is a crucial process in all living organisms and its correct regulation is essential for basic life functions. Homeostasis of iron ions is closely regulated, it usually appears as a component of various proteins and plays role in many oxidation-reduction reactions. Naegleria gruberi is a non-pathogenic, free living protozoon, that serves as a laboratory model for closely related pathogenic Naegleria fowleri. This work focuses on the study of selected metabolites of N. gruberi, that were possible to detect and quantify by the means of modern metabolomic methods, and the influence on culture cultivated in environment with lack of iron ions was shown. The discovery of effect of this condition on the energetic metabolism of this protozoan is an important aspect of understanding the biological processes on cellular level. This method proved a significant influence on certain metabolites and modification of certain metabolic pathways as a direct effect of decreased availability of iron ions. Second part of this work was focused on the enzyme alcohol dehydrogenase, that was found in the genome of this protozoon. Unusual aspects of this enzyme include a N-terminal mitochondrial presequence, prompting about mitochondrial localization, and utilization of iron ion as a prosthetic...
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The effect of iron on the metabolism of the protozoan Trypanosoma brucei
Arbon, Dominik ; Konvalinka, Jan (advisor) ; Grantz Šašková, Klára (referee)
Iron ions are essential components of numerous cell processes. Their utilisation is strictly regulated, since any impairment can have devastating effect on the cell. In living organisms, iron ions are bound to proteins, for storage, transportation, or as a vital part of catalytic centers of enzymes. Transportation of iron ions between different compartments is important for the correct function of the cell. It was recently shown on yeast, how a mitochondrial transporter of iron ions is essential for the synthesis of iron-sulfur clusters of enzymes. This work aims to describe the localization and function of a homologous protein of a parasitical organism Trypanosoma brucei, which causes African trypanosomiasis, also known as sleeping sickness. This parasite is entirely dependent on uptake of iron ions from its host and therefore the utilization of iron ions is studied as a potential therapeutic target. This work is focused on the characterization of protein Mcp17, which is assumed to function as a transporter of iron ions into the mitochondria of T. brucei. Utilizing expression of marked Mcp17, the transporter was confirmed to be localized on the mitochondrial membrane of the cell. Measuring of enzyme activity of selected enzymes indicated that cells with inhibited expression of the gene mcp17...
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